Chronic heart failure affects 4.8 million Americans, with 400,000 new cases every year. The leading cause of this condition includes acute myocardial infarction and repetitive myocardial ischemia. Although current methods of treatment are effective for restoring myocardial blood flow, they cannot prevent cardiac damage caused by ischemia and reperfusion, nor regenerate the lost myocardium. Therapeutic delivery of cardioprotective genes has proven effective in protecting the heart from ischemia/reperfusion injury. Very recently, adult stem cell therapy is emerging as a potential strategy for regenerating lost myocardium. However, the efficacy of this approach is limited by the small number of stem cells that can populate, survive and differentiate in ischemic heart tissues. We hypothesize that these problems can be solved by a hypoxia regulated therapeutic gene transfer using safe and low-risk delivery vectors. Therefore, the objective of this proposal is to develop a combined strategy of regulated gene transfer and stem cell therapy to provide comprehensive protection and regeneration to ischemic hearts. The specific aims are: 1. To protect the heart from ischemic injury by hypoxia-regulated heme oxygenase-1 (HO-1) expression. We will express a cytoprotective enzyme HO-1 in ischemic hearts by recombinant adeno-associated viral(rAAV) vectors and test the protective effects in a murine model of myocardial infarction. 2. To target bone marrow-derived stem cells to ischemic hearts by hypoxia-regulated stromal cell-derived factor-1 (SDF-1) expression. We will deliver a stem cell homing factor SDF-1 specifically to ischemic hearts via rAAV-mediated gene transfer to attract circulating stem cells. 3 .To enhance stem cell survival in ischemic hearts by genetic engineering of stem cells to express hypoxia-regulated HO-I. We will engineer bone marrow-derived stem cells to express HO-1 via ex vivo rAAV infection and evaluate their capacity to survive in ischemic myocardium and to improve cardiac function.